Vertical Transmission of SARS-CoV-2: A Systematic Review

An electronic search was performed on June 13, 2020 on the Embase, PubMed and Scopus databases using the following search terms: (Coronavirus OR COVID-19 OR COVID19 OR SARS-CoV-2 OR SARS-CoV2 OR SARSCoV2) AND (vertical OR pregnancy OR fetal).

Selection of Studies

The electronic search resulted in a total of 2,073 records. Titles and abstracts were reviewed by two authors (WPM, IDESB), who checked for duplicates using the pre-established criteria for screening (studies published in English without limitation regarding the date or the status of the publication).

Data Collection

Data extraction was performed in a standardized way, and the final eligibility was assessed by reading the full text of the articles. We retrieved data regarding the delivery of the potential cases of vertical transmission, as well as themain findings and conclusions of systematic reviews.

Data Synthesis

The 2,073 records were reviewed; 1,000 duplicates and 896 clearly not eligible records were excluded. We evaluated the full text of 177 records, and identified only 9 suspected cases of possible vertical transmission. The only case with sufficient evidence of vertical transmission was reported in France.

Conclusion

The risk of vertical transmission by SARS-CoV-2 is probably very low. Despite several thousands of affected pregnant women, we have identified only one case that has fulfilled sufficient criteria to be confirmed as a case of vertical transmission. Well-designed observational studies evaluating large samples are still necessary to determine the risk of vertical transmission depending on the gestational age at infection.

Keywords:
vertical transmission; SARS-CoV-2; COVID-19; perinatal outcomes; maternal morbidity

Case	Country; city; hospital	Age (years)	Gestational age	Birth weight	Apgar score	Delivery	Main findings	Interval between onset of maternal disease and diagnosis in the neonate	Reasons why vertical transmission is not justified (or justified)
#1Wang et al., ⁷7 Wang S, Guo L, Chen L, LiuW, Cao Y, Zhang J, Feng L. A case report of neonatal 2019 Coronavirus Disease in China. Clin Infect Dis. 2020;71(15):853-857. Doi: 10.1093/cid/ciaa225 https://doi.org/10.1093/cid/ciaa225... Hu et al., ⁸8 Hu X, Gao J, Luo X, Feng L, Liu W, Chen J, et al. Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) vertical transmission in neonates born to mothers with Coronavirus Disease 2019 (COVID-19) pneumonia. Obstet Gynecol. 2020; 136(01):65-67. Doi: 10.1097/AOG.0000000000003926 https://doi.org/10.1097/AOG.000000000000... Yu et al. ⁹9 Yu N, Li W, Kang Q, Xiong Z, Wang S, Lin X, et al. Clinical features and obstetric and neonatal outcomes of pregnant patients with COVID-19 in Wuhan, China: a retrospective, single-centre, descriptive study. Lancet Infect Dis. 2020;20(05):559-564. Doi:10.1016/S1473-3099(20)30176-6 https://doi.org/10.1016/S1473-3099(20)30...	China; Wuhan; Tongji Hospital	34	39 weeks 6 days	3,250 g	8/9	Cesarean	Positive RT-PCR in th oropharynx swab – newborn 36 hours after delivery.	8 hours of maternal symptoms + 36 hours postpartum	Not justified: RT-PCR the in oropharynx swab collected after more than 12 hours of delivery.
#2Dong et al. ¹⁰10 Dong L, Tian J, He S, Zhu C, Wang J, Liu C, Yang J. Possible vertical transmission of SARS-CoV-2 from an infected mother to her newborn. JAMA. 2020;323(18):1846-1848. Doi: 10.1001/jama.2020.4621 https://doi.org/10.1001/jama.2020.4621...	China; Wuhan; Renmin Hospitalof Wuhan University	29	37weeks 6 days	3,120 g	9/10	Cesarean	Positive IgM and IgG 2 hours after delivery;negative RT-PCR in the oropharynx swab;IgM and IgG levels were reduced after 2 weeks;discharged.	25 days	Not justified: discordance among exams and negative RT-PCR in the oropharynx swab.
#3Zamaniyan et al. ¹¹11 Zamaniyan M, Ebadi A, Aghajanpoor Mir S, Rahmani Z, Haghshenas M, Azizi S. Preterm delivery, maternal death, and vertical transmission in a pregnant woman with COVID-19 infection. Prenat Diagn. 2020 [ahead of print]	Iran; Sari; Imam Khomeini Hospital	22	32 weeks	2,350 g	8/9	Cesarean	Positive RT-PCR in the amniotic fluid collected during cesarean section (contamination?); negative RT-PCR in the oropharynx swab of the newborn; maternal death postpartum.	7 days	Not justified: positive RT-PCR in the amniotic fluid, but with the possibility of contamination with no other confirmation of the virus.
#4Li et al. ⁵5 Li N, Han L, Peng M, Lv Y, Ouyang Y, Liu K, et al. Maternal and Neonatal Outcomes of Pregnant Women With Coronavirus Disease 2019 (COVID-19) Pneumonia: A Case-Control Study. Clin Infect Dis. 2020;71(16):2035-2041 and Ferrazzi et al. ¹²12 Ferrazzi E, Frigerio L, Savasi V, Vergani P, Prefumo F, Barresi S, et al. Vaginal delivery in SARS-CoV-2-infected pregnant women in Northern Italy: a retrospective analysis. BJOG. 2020;127(09): 1116-1121. Doi: 10.1111/1471-0528.16278 https://doi.org/10.1111/1471-0528.16278...	China; Wuhan; Hubei Provincial Maternal and Child Health Center; ⁵5 Li N, Han L, Peng M, Lv Y, Ouyang Y, Liu K, et al. Maternal and Neonatal Outcomes of Pregnant Women With Coronavirus Disease 2019 (COVID-19) Pneumonia: A Case-Control Study. Clin Infect Dis. 2020;71(16):2035-2041 and Italy; Lombardy and Units of Padua and Modena ¹²12 Ferrazzi E, Frigerio L, Savasi V, Vergani P, Prefumo F, Barresi S, et al. Vaginal delivery in SARS-CoV-2-infected pregnant women in Northern Italy: a retrospective analysis. BJOG. 2020;127(09): 1116-1121. Doi: 10.1111/1471-0528.16278 https://doi.org/10.1111/1471-0528.16278...	NR	NR	NR	NR	Vaginal	Positive RT-PCR in two newborns. In these two cases, because viral testing was not performed immediately after birth, postpartum transmission cannot be excluded.	Not informed	Not justified: the swab test was not performed shortly after birth.
#6Alzamora et al. ¹³13 AlzamoraMC, Paredes T, Caceres D,Webb CM, Valdez LM, La Rosa M. Severe COVID-19 during pregnancy and possible vertical transmission. Am J Perinatol. 2020;37(08):861-865. Doi: 10.1055/s-0040-1710050 https://doi.org/10.1055/s-0040-1710050...	Peru; Lima; British American Hospital	41	33 weeks	2,970 g	6/8	Cesarean	Positive RT-PCR in the nasopharyngeal swab – newborn 16 hours after delivery. Repeated in 48 hours: also positive.	5 days	Not justified: RT-PCR in the nasopharyngeal swab collected 12 hours after delivery.
#7Vivanti et al. ¹⁴14 Vivanti AJ, Vauloup-Fellous C, Prevot S, Zupan V, Suffee C, Do Cao J, Benachi A, et al. Transplacental transmission of SARS-CoV-2 infection. Nat Commun. 2020;11(01):3572. Doi: 10.1038/s41467-020-17436-6 https://doi.org/10.1038/s41467-020-17436...	France; Paris Saclay University Hospitals	23	35 weeks 5 days	2,540 g	4/1	Cesarean	Amniotic fluid collected during cesarean section positive on RT-PCR (Genes E and S).Nasopharyngeal and rectal swabs collected within 1 hour, 3 days and 18 days of life were positive on RT-PCR (Genes E and S).Blood and non-bronchoscopic bronchoalveolar lavage fluid collected before extubation (6 hours after delivery) positive on RT-PCR (Genes E and S).	5 days	Justified: positive RT-PCR in the amniotic fluid and in the neonate blood sample collected before 12 hours of delivery.
#8Mehta et al. ¹⁵15 Mehta H, Ivanovic S, Cronin A, VanBrunt L, Mistry N, Miller R, Yodice P, et al. Novel coronavirus-related acute respiratory distress syndrome in a patient with twin pregnancy: A case report. Case Rep Womens Health. 2020;27:e00220. Doi: 10.1016/j.crwh.2020.e00220 https://doi.org/10.1016/j.crwh.2020.e002...	United States; Liningston; Saint Barnabas Medical Center	39	27 weeks	Baby A: 925 g;Baby B: 1,050 g	Baby A: 1/3;Baby B: 5/6	Cesarean	Twin A tested positive and twin B tested negative for SARS-CoV-2 at 72 hours, and it is not clear what type of test was performed. The authors believe that twin A tested positive due to vertical transmission.	14 days	Not justified: the type of test performed is not described properly, and it was performed 12 hours after delivery.
#9Sun et al. ¹⁶16 Sun M, Xu G, Yang Y, Tao Y, Pian-Smith M, Madhavan V, et al. Evidence of mother-to-newborn infection with COVID-19. Br J Anaesth. 2020;125(02):e245-e247. Doi: 10.1016/j.bja.2020.04.066 https://doi.org/10.1016/j.bja.2020.04.06...	China; Henan; Henan Provincial People's Hospital	28	37 weeks	Not informed	9/9	Cesarean	Obstetricians, anesthesiologists, neonatologists, and nurses wore full personal protective equipment, including an N95 mask, eye goggles, face shield, and a top-to-bottom tight-fitting gown, entering the operating theaters ∼ 5 minutes before the patients. Neonate tested positive for SARS-CoV-2 at day 6 postpartum.	9 days of maternal symptoms + 6 postnatal days	Not justified: RT-PCR in the oropharynx swab collected 12 hours after delivery.

Systematic reviews
Di Mascio et al. (2020): ¹⁷17 Di Mascio D, Khalil A, Saccone G, Rizzo G, Buca D, LiberatiM, et al. Outcome of coronavirus spectrum infections (SARS, MERS, COVID-19) during pregnancy: a systematic review and metaanalysis. Am J Obstet Gynecol MFM. 2020;2(02):100107. Doi: 10.1016/j.ajogmf.2020.100107 https://doi.org/10.1016/j.ajogmf.2020.10... “In mothers infected with coronavirus infections, including COVID-19, > 90% of whom also had pneumonia, PTB is the most common adverse pregnancy outcome. Miscarriage, preeclampsia, cesarean, and perinatal death (7-11%) were also more common than in the general population. There have been no published cases of clinical evidence of vertical transmission.”
Della Gatta et al. (2020): ¹⁸18 Della Gatta AN, Rizzo R, Pilu G, Simonazzi G. Coronavirus disease 2019 during pregnancy: a systematic review of reported cases. Am J Obstet Gynecol. 2020;223(01):36-41. Doi: 10.1016/j.ajog.2020.04.013 https://doi.org/10.1016/j.ajog.2020.04.0... “The available data on COVID-19 illness in pregnant patients do not provide a clear conclusion into the clinical implications for mother and fetus. The outcome thus far described is favorable, but fetal and maternal risks should be underestimated. Although preterm delivery was mostly the consequence of elective interventions, a trend towards spontaneous prematurity is present. It is essential that future studies provide more detailed information on maternal and fetal conditions, as well as the rationale for obstetric interventions. Experience, thus far, is limited to patients that developed the disease in late gestation and were delivered shortly after the diagnosis. The fetal consequences of long-standing infections occurring in early gestation are unknown.”
Zaigham and Andersson (2020): ¹⁹19 Zaigham M, Andersson O. Maternal and perinatal outcomes with COVID-19: A systematic review of 108 pregnancies. Acta Obstet Gynecol Scand. 2020;99(07):823-829. Doi: 10.1111/aogs.13867 https://doi.org/10.1111/aogs.13867... “Current evidence suggests the possibility of severe maternal morbidity requiring ICU admission and perinatal death with COVID-19 infection in pregnancy. Maternal-fetal transmission of the SARSCoV-2 virus was not detected in the majority of the reported cases, although one neonate had a positive qRT-PCR 36 hours after birth despite being isolated from the mother. Careful monitoring of pregnancies with COVID-19 and measures to prevent neonatal infection are warranted.”
Abdollahpour and Khadivzadeh (2020): ²⁰20 Abdollahpour S, Khadivzadeh T. Improving the quality of care in pregnancy and childbirth with coronavirus (COVID-19): a systematic review. J Matern Fetal Neonatal Med. 2020;•••:1-9. Doi: 10.1080/14767058.2020.1759540 [ahead of print] https://doi.org/10.1080/14767058.2020.17... “No trustworthy evidence is available yet to support the possibility of vertical transmission of COVID-19 infection from the mother–baby. Mother-to-child transmission of respiratory viruses mostly happens via the birth canal and during breastfeeding or close contact among health care providers, family members. To our knowledge, no article has reconnoitered that reporting a newly vertically transmitted case.”
Banaei et al. (2020): ²¹21 Banaei M, Ghasemi V, Saei Ghare Naz M, Kiani Z, Rashidi-Fakari F, Banaei S, et al. Obstetrics and neonatal outcomes in pregnant women with COVID-19: a systematic review. Iran J Public Health. 2020;49(Suppl 1):38-47 “There was some evidence about neonates COVID-19 in the included studies, but it is not clear whether the source of the infection in these neonates is from the mother or from the environment. In the majority of studies, there was no evidence of vertical transmission. In most studies, the neonates were separated from the mother after birth to reduce the chance of transmission, but there is also currently insufficient evidence regarding the mother/baby separation. If the mother is severely or critically ill, separation should be considered. The result of a review showed that in SARS vertical transmissions were not seen.
Duran et al. (2020): ²²22 Duran P, Berman S, Niermeyer S, Jaenisch T, Forster T, Ponce de León RG, et al. COVID-19 and newborn health: systematic review. Rev Panam Salud Publica. 2020;44:e54. Doi: 10.26633/RPSP.2020.54 https://doi.org/10.26633/RPSP.2020.54... “There is still no evidence supporting vertical transmission of COVID-19. Some newborns were positive for COVID-19 in spite of the reported use of preventive measures during and after delivery, but even in these cases there was no evidence supporting vertical transmission.”
Elshafeey et al. (2020): ²³23 Elshafeey F, Magdi R, Hindi N, Elshebiny M, Farrag N, Mahdy S, et al. A systematic scoping review of COVID-19 during pregnancy and childbirth. Int J Gynaecol Obstet. 2020;150(01):47-52. Doi: 10.1002/ijgo.13182 https://doi.org/10.1002/ijgo.13182... “We extracted data regarding potential vertical transmission. In four neonates who had RT-PCR confirmed infection, samples from cord blood and amniotic fluid were negative. Based on the available data, we are uncertain of the mode of transmission, since there is no evidence that these four cases were the result of a vertical transmission.”
Gordon et al. (2020): ²⁴24 Gordon M, Kagalwala T, Rezk K, Rawlingson C, Ahmed MI, Guleri A. Rapid systematic review of neonatal COVID-19 including a case of presumed vertical transmission. BMJ Paediatr Open. 2020;4 (01):e000718. Doi: 10.1136/bmjpo-2020-000718 https://doi.org/10.1136/bmjpo-2020-00071... “Neonatal infection is uncommon, with only two previously reported cases likely to be of vertical transmission. The case we report is still RT-PCR-positive on day 28, and is asymptomatic.”
Huntley et al. (2020): ²⁵25 Huntley BJF, Huntley ES, Di Mascio D, Chen T, Berghella V, Chauhan SP. Rates of maternal and perinatal mortality and vertical transmission in pregnancies complicated by Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-Co-V-2) infection: a systematic review. Obstet Gynecol. 2020;136(02):303-312. Doi: 10.1097/AOG.0000000000004010 https://doi.org/10.1097/AOG.000000000000... “Data from early in the pandemic is reassuring that there are low rates of maternal and neonatal mortality and vertical transmission with SARS-CoV-2.”
Juan et al. (2020): ²⁶26 Juan J, Gil MM, Rong Z, Zhang Y, Yang H, Poon LC. Effect of coronavirus disease 2019 (COVID-19) on maternal, perinatal and neonatal outcome: systematic review. Ultrasound Obstet Gynecol. 2020;56(01):15-27. Doi: 10.1002/uog.22088 https://doi.org/10.1002/uog.22088... “Despite the increasing number of published studies on COVID-19 in pregnancy, there are insufficient good-quality data to draw unbiased conclusions with regard to the severity of the disease or specific complications of COVID-19 in pregnant women, as well as vertical transmission, perinatal and neonatal complications.”
Kasraeian et al. (2020): ²⁷27 Kasraeian M, Zare M, Vafaei H, Asadi N, Faraji A, Bazrafshan K, Roozmeh S. COVID-19 pneumonia and pregnancy; a systematic review and meta-analysis. J Matern Fetal Neonatal Med. 2020; •••:1-8. Doi: 10.1080/14767058.2020.1763952 [ahead of print] https://doi.org/10.1080/14767058.2020.17... “Currently, no evidence of vertical transmission has been suggested at least in late pregnancy. No hazards have been detected for fetuses or neonates. Although pregnant women are at an immunosuppressive state due to the physiological changes during pregnancy, most patients suffered from mild or moderate COVID-19 pneumonia with no pregnancy loss, proposing a similar pattern of the clinical characteristics of COVID-19 pneumonia to that of other adult populations.”
Ludvigsson (2020): ²⁸28 Ludvigsson JF. Systematic review of COVID-19 in children shows milder cases and a better prognosis than adults. Acta Paediatr. 2020;109(06):1088-1095. Doi: 10.1111/apa.15270 https://doi.org/10.1111/apa.15270... “Newborn infants have developed symptomatic COVID-19, but evidence of vertical intrauterine transmission was scarce.”
Muhidin et al. (2020): ²⁹29 Muhidin S, Behboodi Moghadam Z, Vizheh M. Analysis of maternal Coronavirus Infections and neonates born to mothers with 2019-nCoV; a systematic review. Arch Acad Emerg Med. 2020;8 (01):e49 “No fetal infection through intrauterine vertical transmission was reported.”
Smith et al. (2020) ³⁰30 Smith V, Seo D,Warty R, Payne O, Salih M, Chin KL, et al. Maternal and neonatal outcomes associated with COVID-19 infection: A systematic review. PLoS One. 2020;15(06):e0234187. Doi: 10.1371/journal.pone.0234187 https://doi.org/10.1371/journal.pone.023... : “It is unclear if this is evidence of vertical transmission or if it was contracted post-delivery due to delayed RT-PCR testing 36 hours from birth. The evidence for vertical transmission appears equivocal.”
Walker et al. (2020): ³¹31 Walker KF, O'Donoghue K, Grace N, Dorling J, Comeau JL, Li W, Thornton JG. Maternal transmission of SARS-COV-2 to the neonate, and possible routes for such transmission: a systematic review and critical analysis. BJOG. 2020;127(11):1324-1336. Doi: 10.1111/1471-0528.16362 https://doi.org/10.1111/1471-0528.16362... “To date, there have been 28 cases published where the possibility for vertical transmission to have occurred have been reported. To confirm definite vertical transmission, it has been proposed that detection of the virus by PCR in either umbilical cord blood, neonatal blood collected within the first 12 hours of birth, or amniotic fluid collected prior to rupture of membranes is needed. In no cases reported to date have these criteria been met although some report negative testing. A few cases deserve special mention: one case reports a positive nasopharyngeal swab in the neonate on the day of birth. The authors do not describe any procedure or care taken to clean the infant's oropharynx / mouth/nares / face prior to procuring the swab and we speculate that the presence of the virus may be due to contamination by maternal stool. Of note, the virus was not detected on repeat swab and the infant remained well. The presence of IgG would be maternal, so again not diagnostic. The UKOSS study reports 12/24 cases of possible vertical transmission. Limited information is given for the 12 neonates but 6/12 infants tested positive for COVID-19 within 12 hours of birth. It is unclear what method of testing was used and if this was a nasopharyngeal swab without precautions to clean the infant prior to testing, may again be a result of contamination. In another case, a positive nasopharyngeal swab in the neonate on the day of birth occurred after careful separation of the baby and cleansing of the baby prior to taking the swab.”
Yang and Liu (2020) ³²32 Yang Z, Liu Y. Vertical Transmission of Severe Acute Respiratory Syndrome Coronavirus 2: A Systematic Review. Am J Perinatol. 2020;37(10):1055-1060. Doi: 10.1055/s-0040-1712161 https://doi.org/10.1055/s-0040-1712161... : “There is currently no direct evidence to support intrauterine vertical transmission of SARS-CoV-2. Additional RT-PCR tests on amniotic fluid, placenta, and cord blood are needed to ascertain the possibility of intrauterine vertical transmission. For pregnant women infected during their first and second trimesters, further studies focusing on long-term outcomes are needed.”
Yang et al. (2020): ³³33 Yang Z, Wang M, Zhu Z, Liu Y. Coronavirus disease 2019 (COVID- 19) and pregnancy: a systematic review. J Matern Fetal Neonatal Med. 2020;•••:1-4. Doi: 10.1080/14767058.2020.1759541 [ahead of print] https://doi.org/10.1080/14767058.2020.17... “Currently, there is no direct evidence suggesting that COVID-19 in pregnancy could lead to fetal infection via intrauterine vertical transmission. Long-term outcomes and potential intrauterine vertical transmission need further analysis.”

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[1] Address for correspondence Ionara Diniz Evangelista Santos Barcelos, MD, PhD, Departmento de Ginecologia e Obstetrícia, Universidade Estadual do Oeste do Paraná, Cascavel, Paraná, PR, Brazil (e-mail: ionarabarcelos@hotmail.com).